Intestinal absorption, intestinal distribution, and excretion of (14C) labelled hyoscine N-butylbromide (butylscopolamine) in the rat

Butylscopolamine was labelled with ¹⁴C and its gastrointestinal absorption, biliary and urinary excretion, enterohepatic circulation and gastrointestinal distribution were examined in anaesthetized rats. Biliary excretion was the main elimination route of intra-portally administered [¹⁴C]butylscopolamine, with 42% of the dose recovered in the bile during 12 h. About 6% of the radioactivity administered orally as [¹⁴C]butylscopolamine was excreted in the bile and 1.2 % in the urine during 24 h, which indicates poor gastrointestinal absorption of butylscopolamine in the rat. When collected radioactive bile was readministered intrajejunally, only about 7% of the radioactivity was recovered in bile and urine during 12 h, which suggests that only a small fraction of butylscopolamine and its metabolites engage in an enterohepatic circulation. After oral administration of [¹⁴C]butylscopolamine, radioactivity was found to accumulate in the wall of the distal small intestine, and about 20% of the dose was found in this tissue 24 h after drug administration. As a result, local anti-acetylcholine effects of butylscopolamine might be expected.     

Species differences in the metabolism of a tricyclic psychotropic agent,SQ 11,290-C

The metabolism of SQ 11,290-¹⁴C (4-[3-(7-chloro-5,11-dihydrodibenz[b,e]-[1,4]-oxazepin-5-yl)propyl]-α,β-¹⁴C₂-1-piperazineethanol, dihydrochloride) was studied in mice, rats, guinea pigs, hamsters, New Zealand White or Dutch rabbits, monkeys and man after po administration. The excretion of SQ 11,290-¹⁴C, its metabolites, or both, was chiefly in the feces (with the exception of hamsters and man). Rats and rabbits of either strain excreted 2–5% of the dose—mice and hamsters excreted 20–42%—as ¹⁴CO₂. Hamsters appeared to excrete radioactivity in a quantitative manner most similar to that observed in man, but the metabolites found in the urine and feces of these 2 species were not similar. The disposition of SQ 11,290-¹⁴C in albino and pigmented rabbits cannot be distinguished on the basis of the excretion of radioactivity, but different metabolites appear to be excreted in the urine. No unchanged SQ 11,290-¹⁴C was detected in the excreta of humans. One percent of the dose or less was present as unchanged SQ 11,290-¹⁴C in the urine of any animal species. In the feces, an average of 2–6% of the dose was excreted by animal species as unchanged SQ 11,290-¹⁴C. Whereas albino rabbits excreted in the feces only 3.6% of the dose as unchanged drug, Dutch rabbits excreted about 16.7% of the dose as unchanged drug. In those human subjects excreting large amounts of radioactivity as ¹⁴CO₂, cleavage or degradation of the side chain, or both, rather than hydroxylation of the ring system as had been found previously in dogs, appeared to be a major metabolic pathway.     

The Metabolism of Tolamolol* in the Mouse,Rat, Guinea-pig,Rabbit and Dog

1. [³H, ¹⁴C]Tolamolol was well absorbed after oral administration to mice, rats, guinea-pigs, rabbits and dogs.

2. The major route for excretion of. radioactivity by mice, rats and guineapigs was the faeces; in rabbits the major route was the urine. Dogs excreted similar amounts of radioactivity by both routes. Biliary excretion of radioactivity by the rat and guineapig was demonstrated.

3. Tolamolol was extensively metabolized by all five species. The major metabolite in mice, rats, guinea-pigs and rabbits was the product of hydroxylation of the tolyl ring, which was excreted as such and as the glucuronide and sulphate conjugates.

4. In the dog the major metabolite was the acid resulting from hydrolysis of the carbamoyl group. This acid was also excreted by the rabbit, but was only a minor metabolite in the other species studied.     

The absorption, tissue distribution and excretion of di-n-octyltin dichloride in rats

In this study the absorption, tissue distribution and excretion of 14C-labeled di-n-octyltin dichloride ([14C]DOTC) in rats were investigated after oral and intravenous (i.v.) administration. Although after i.v. administration with 1.2 mg [14C]DOTC/kg body weight the tissue radioactivity was about 3-4 times higher than after oral administration with 6.3 mg [14C]DOTC/kg body weight, the relative tissue accumulation was found to be the same after the oral and i.v. dosage. The highest amount of radioactivity was found in liver and kidney, and to a lesser degree in adrenal, pituitary and thyroid glands. The lowest activity was recovered from blood and brain. No selective accumulation was observed in thymus, although it has been reported that thymus atrophy is the most sensitive parameter of DOTC toxicity in rats. For all tissues a time dependent decrease in radioactivity was found, except for kidney. The excretion of radioactivity in feces and urine was determined after a single i.v. or oral dose of 1.2 and 2 mg [14C]DOTC, respectively. After i.v. administration most of the radioactivity was excreted in the feces which was characterized by a biphasic excretion pattern. In orally treated rats more than 80% of the radioactivity was already excreted in the feces during the first day after administration. This indicated that only a small part of the DOTC was absorbed, which was calculated to be approximately 20% of the dose. Similar half-life values of 8.3 and 8.9 days were obtained from the fecal excretion of radioactivity after the i.v. and oral administration, respectively. The urinary excretion of radioactivity appeared to be independent of the body burden, since the daily amount of radioactivity excreted in urine was nearly the same independent of the route of administration as well as the time after administration.     

Blood level, distribution, metabolite pattern and excretion of [14C]alinidine in mice and rats

Following oral and intravenous administration the absorption, distribution, metabolite pattern and excretion of [14C]alinidine, a drug with specific bradycardic efficacy, was studied in mice and rats. [14C]alinidine was rapidly and extensively absorbed. The distribution of radio-labelled drug over the entire animal body was rapid as indicated by blood level curves as well as by whole body autoradiography. In both species radioactive compounds were eliminated from blood with half-lives ranging from 5.6 h to 7.4 h. More than 50% of the renally excreted radioactivity was a uniform substance behaving in in TLC and HPLC experiments like the drug administered. From rat urine this compound could be identified as [14C]alinidine using mass spectrometry. In mice and rats no definite substance with clonidine-like chromatographic properties was found. Biliary excretion was demonstrated in both species. The renal portion of the total radioactivity elimination was 67.2-70.1% of the dose administered in mice and 68.1-85.1% in rats. Total excretion was 85.1-101.3% of radioactivity given and was complete 3-4 days after [14C]alinidine administration. No significant differences in pharmacokinetic behavior in mice and rats could be found.     

Nadolol: placental transfer and excretion in the milk of rats.

The transfer of radioactivity from maternal blood to the fetuses of pregnant rats was studied after they had been dosed orally with 100 mg/kg of [¹⁴C]nadolol (2,3-cis-5-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-1,2,3,4-tetrahydro-2,3-naphthalenediol) on Days 12, 15, and 18 of gestation. On Day 12 of gestation, during the time of organogenesis, radioactivity crossed the placental barrier to the fetuses; however, the extent of this transfer was significantly reduced on Days 15 and 18 of gestation. The excretion of radioactivity was studied in the milk of lactating rats that had been given oral 100-mg/kg doses of [¹⁴C]nadolol. Twelve or 30 hr after the dams had been dosed, radioactivity was presentin greater concentrations in milk than it was in either blood or plasma. The amount of radioactivity found in the pups that had been allowed to suckle during the intervals of 0 to 6 and 12 to 24 hr after the dams had been dosed was, for both intervals, an average of 0.041% of the dose.     

Absorption,distribution, metabolism and excretion of novel phosphodiesterase type 4 inhibitor ASP3258 in rats

The potent and selective phosphodiesterase 4 inhibitor ASP3258 is a novel therapeutic agent for asthma and chronic obstructive pulmonary disease (COPD). After a single oral administration to rats, ASP3258 is rapidly absorbed with a bioavailability of 106%. In situ absorption data indicated that ASP3258 is mainly absorbed in the small intestine. Tissue distribution data after oral administration of ¹⁴C‐ASP3258 showed rapid and extensive distribution to various tissues. Excluding the gastrointestinal tract, the tissues with the highest concentrations were liver, heart and plasma. Liquid chromatography‐nuclear magnetic resonance spectroscopy data revealed that O‐glucuronidation of the carboxylic acid moiety of ASP3258 (formation of an acyl glucuronide) plays a key role in metabolism. No indication was found that the acyl glucuronide reacted with proteins in plasma or tissues. When ¹⁴C‐ASP3258 was orally administered to intact rats, urinary and fecal excretion accounted for 1.3% and 100.6% of the administered radioactivity, respectively. After a single oral administration of ¹⁴C‐ASP3258 to bile‐cannulated rats, urinary and biliary excretion accounted for 0.7% and 93.8% of the administered radioactivity, respectively. These findings suggest that fecal excretion via bile plays an important role in the elimination of ASP3258‐derived radioactivity. In vitro metabolic profiles were relatively similar among the species examined, suggesting that our findings in rats may help us to understand pharmacokinetics, efficacy and safety profiles in humans and other species. Copyright © 2014 John Wiley & Sons, Ltd.     

Radioisotope studies of purine metabolism during administration of guanine and allopurinol in the pig

In pigs pre-fed guanine, some 33 per cent of [8-¹⁴C]guanine administered orally appeared in the urine in 24 hr, principally in the form of allantoin. Little incorporation (less than 1 per cent) of radioactivity into body tissues occurred and only 5 per cent of the radioactivity could be found in the faeces.When allopurinol was added to the guanine diet the pattern of excretion of [8-¹⁴C]-guanine changed considerably. Only 11 per cent of the radioactivity was recovered from the urine in 24 hr while 83 per cent appeared in the faeces in 3 days. Again, less than 1 per cent of the radioactivity was found in the tissues at slaughter.Intravenous administration of [8-¹⁴C]guanine to a pig on the above mixture resulted in the rapid incorporation of approximately 50 per cent of the radioactivity into body tissues with a slow subsequent daily excretion of approximately 2 per cent of this radioactivity in faeces and urine. The finding of 13 per cent of the radioactivity in the faeces is considered evidence of purine excretion into the gut. The recovery of urinary radioactivity (34 per cent of dose) principally in xanthine, but also in hypoxanthine, showed the existence of a rapid additional route of guanine catabolism via hypoxanthine. Experimental evidence is also presented to demonstrate the existence of a reciprocal relationship between urinary [¹⁴C]hypoxanthine and allopurinol riboside excretion suggesting competitive inhibition of allopurinol riboside formation by hypoxanthine in vivo.In the allopurinol treated pig, orally administered [6-¹⁴C]allopurinol was rapidly absorbed and almost totally excreted in the urine in 24 hr (90 per cent). The remainder of the radioactivity (approximately 7 per cent) was excreted in the faeces in 3 days and no radioactivity could be detected in tissue nucleic acids or in tissues to any extent (less than 0.01 per cent of the dose).The significance of these results in relation to the metabolic studies is discussed.     

The metabolism of the surfactants dodecyl sulfonate and hexadecyl sulfonate in the rat.

When [1-¹⁴C]dodecyl sulfonate and [1-¹⁴C]hexadecyl sulfonate were administered orally and ip to free-ranging rats and iv to anesthetized rats, the major route of excretion of radioactivity was urinary. Small amounts only of parent surfactant appeared in the feces of animals dosed orally with [1-¹⁴C]dodecyl sulfonate, but large amounts of [1-¹⁴C]hexadecyl sulfonate were found in the feces of animals dosed similarly with this surfactant. Thus, fecal radioactivity represents incomplete absorption of material from the gastrointestinal tract, the permeability of which may depend upon the water solubility of the administered surfactant. The pattern of excretion with either compound was essentially unchanged when animals were pretreated with an antibiotic, and thus the gut flora play no significant part in the metabolism or absorption of these surfactants. No biliary elimination with either surfactant was detected following the iv administration, confirming that the fecal radioactivity represented unabsorbed material. The intraperitoneal administration of dodecyl [³⁵S]sulfonate to rats and analysis of the urinary products showed that no desulfonation takes place. Analysis of the urine of rats following the administration of either [1-¹⁴C]dodecyl sulfonate or [1-¹⁴C]hexadecyl sulfonate revealed the same single metabolite from both surfactants. This metabolite was purifed and identified as butyric acid 4-sulfonate by radioactive glc, mass spectrometry, and cochromatography of its dimethyl derivative. The identity of the urinary metabolite indicates that both dodecyl sulfonate and hexadecyl sulfonate are degraded in the rat by ω,β-oxidation. Whole body autoradiography demonstrates that the liver is the major site of metabolism regardless of the route of administration.     

The metabolism of carfecillin in rat,dog and man

1. The absorption of the phenol moiety of [phenol-¹⁴C]carfecillin following oral administration to rat, dog and man was extensive, since 95%, 73% and 99% of the administered radioactivity respectively was recovered in the urine. In contrast, less than half of the carbenicillin moiety of carfecillin was absorbed after oral administration, as judged by excretion studies using [carbenicillin-¹⁴C]carfecillin in intact and bile-duct cannulated animals.

2. The patterns of radiometabolites in the urines of rat, dog and man following single oral administration of [phenol-¹⁴C]carfecillin were determined by chromatography and radioassay. In two men, the majority of a dose was excreted as phenylsulphate (71%) and phenylglucuronide (16%) with the sulphate and glucuronic acid conjugates of quinol representing small amounts of the urinary radioactivity. Similar metabolic patterns were observed in the rat and dog following oral administration of either [¹⁴C]phenol or [phenol-¹⁴C]carfecillin, although some saturation of sulphate conjugation was apparent at the dose levels employed.     

Absorption, distribution, and excretion of DJ-927, a novel orally effective taxane, in mice, dogs, and monkeys

DJ-927, currently undergoing Phase I clinical trial, is a new orally effective taxane with potent antitumor effects. The absorption, tissue distribution, and excretion of DJ-927 were investigated in mice, dogs, and monkeys after a single oral administration. After oral administration of [14C]DJ-927, radioactivity was rapidly absorbed, with the Cmax occurring within 1-2 h in all species. The blood and plasma radioactivity elimination was biphasic and species-dependent. Elimination half-life of plasma in dogs was much longer than those in monkeys or mice. In mice, radioactivity was rapidly distributed to all tissues except for the central nervous system, especially to adrenal glands, liver, pituitary glands, kidneys, lungs, and spleen. In all species, radioactivity was mainly excreted in feces. Following a single oral administration to mice, more than 80% of the radioactivity was excreted within 48 h; in dogs and monkeys, 80% of the radioactivity was excreted within 168 h. Urinary excretion was less than 7% of radioactive dose in all species. In vitro plasma protein binding of [14C]DJ-927 in the mouse, dog, and monkey plasma ranged from 92-98%. These studies showed that, the novel oral taxane DJ-927 was rapidly absorbed in all three species when administered by the oral route. The long biological half-life and slow elimination of radioactivity were distinctive in particular, compared with commercial taxanes. DJ-927 (as parent compound and its metabolites) is widely distributed to tissues except the brain. These preclinical data are useful for the design of clinical trials of DJ-927 and also for their interpretation.     

The absorption,distribution and excretion of [14C]lormetazepam in dogs,rabbits, rats and rhesus monkeys

1. Oral doses of [¹⁴C]lormetazepam (0.05–0.25mg/kg) were rapidly and almost completely absorbed by female dogs, rabbits, rats and rhesus monkeys. Elimination of ¹⁴C was rapid and similar after oral or i.v. doses.

2. Rats excreted most of the dose in the faeces (76%), whereas dogs, rabbits and monkeys excreted it in the urine (60, 85 and 80% respectively. The urinary excretion half-lives of ¹⁴C from monkeys (c. 10?h), rabbits (c. 12?h), dogs (c. 14?h) and rats (c. 8?h) paralleled the rate of decline of plasma concn. of ¹⁴C.

3. Biliary excretion of lormetazepam and/or its metabolites occurred in rats (83%), dogs (48%) and possibly to a lesser extent in the other two species. Enterohepatic circulation of ¹⁴C in rat was extensive (47%), but not of long duration, and probably occurred in dog and rabbit.

4. Mean peak plasma concn. of ¹⁴C in dogs, rabbits, rats and monkeys of 190, 29, 42 and 280 ng equiv./ml respectively were reached at 1.5, 1, 0.5 and 1?h. A.U.C. values after oral and i.v. doses were similar in dogs, rats and monkeys. In these species, plasma concn. declined biphasically with t_1/2 values of about 15, 14 and 11?h respectively.

5. Concn. of ¹⁴C in rat tissues, particularly in blood cells, liver, kidneys and gut, were several times greater than those in plasma after single or multiple oral doses. Some accumulation in tissues occurred after multiple doses, presumably partly because of accumulation of ¹⁴C in blood cells.

6. Transplacental transfer of ¹⁴C into foetuses of rats or rabbits was low. In rabbits, maternal: foetal concn. ratios ranged between 9 and 26 : 1 after oral or i.v. doses.

7. The excretion (rats and dogs), or plasma ¹⁴C concn.-time profiles (dogs), were not altered during multiple oral doses for 21 days.     

Blood level, metabolism and excretion of [14C]-brotizolam in mice

Blood level, metabolite pattern and excretion of [14C]-brotizolam, a hypnotic drug, were studied in mice following oral administration. [14C]-Brotizolam was rapidly absorbed which was indicated by a Tmax of the blood level of 0.5 h. Radioactive compounds were eliminated from the blood with a half-life of 5.6 h. Total excretion of radioactivity, the renal portion of which was 22.4%, was complete after 4 days. [14C]-Brotizolam was almost completely metabolized. Using TLC, HPLC and radioactivity measurement, the main metabolite in bile, urine and plasma was found to be brotizolam hydroxylated at the methyl group. Other major metabolites were brotizolam hydroxylated at the diazepine ring and a combination of both hydroxylations. In the bile, all metabolites were conjugated. The metabolism of brotizolam in mice is similar to that in dogs, monkeys and man but not in rats.     

Metabolism of Linoleamides: II. Absorption,Distribution, Excretion and Metabolism of N-[α-Phenyl-β-(p-tolyl)ethyl] linoleamide

1. Absorption, distribution, excretion and metabolism of (-)N-[α-phenyl-β-(p-tolyl)ethyl][¹⁴C]linoleamide (¹⁴C-PTLA) were studied in rats and dogs. Faecal excretion of PTLA was studied in dogs and men by g.l.c.

2. ¹⁴C-PTLA (10 mg/kg) given orally to rats resulted in urinary and faecal excretion of radioactivity of 2 and 93 %, respectively, by male rats and 8 and 87% by female rats in 48 h. Faecal excretion of PTLA in men was similar to that in rats.

3. Distribution of radioactivity in rats and dogs after oral administration of ¹⁴C-PTLA showed that a major part of the dose was not absorbed.

4. N-[α-Phenyl-β-(p-tolyl)ethyl]succinic acid monoamide and N-[α-phenyl-β-(p-tolyl)ethyl]glutaric acid monoamide were detected in the urine of rats dosed orally with ¹⁴C-PTLA.     

Metabolic fate of the new angiotensin-converting enzyme inhibitor imidapril in animals. 1st communication: absorption, pharmacokinetics and excretion in rats and dogs.

Imidapril hydrochloride ((-)-(4S)-3-[(2S)-2-[[(1S)-1-ethoxycarbonyl-3- phenylpropyl]amino]propionyl]-1-methyl-2-oxoimidazolidine-4-carboxylic acid hydrochloride, imidapril, TA-6366, CAS 89396-94-1) is an ester prodrug of the angiotensin-converting enzyme (ACE) inhibitor, 6366 A (CAS 89371-44-8). Absorption, pharmacokinetics and excretion of imidapril were studied in rats and dogs after oral and intravenous administration of [N-methyl-14C]-imidapril and [N-methyl-14C]-6366 A (1 mg/kg). Following oral administration of 14C-labeled imidapril and 6366 A to rats, plasma concentrations of radioactivity were much higher after [N-methyl-14C]-imidapril dosing than after [N-methyl-14C]-6366 A dosing at all time points. Imidapril was relatively rapidly absorbed from the digestive tract and easily metabolized to the pharmacologically active 6366 A after oral dosing in the rats and dogs. Thus, imidapril proved to be an orally usable 6366 A prodrug. More than 62% and 38% of the dose were assumed to be absorbed from the gastrointestinal tract in the rats and dogs, respectively. The in situ absorption study showed that [N-methyl-14C]-imidapril was absorbed from nearly the entire rat small intestine, especially from the jejunum, but hardly absorbed from the stomach. After oral administration, peak levels of radioactivity in the plasma occurred at 1 h in rats and 30 min to 2 h in dogs. The disappearance of unchanged drug from the plasma was much faster in rats than in dogs.(ABSTRACT TRUNCATED AT 250 WORDS)     

Percutaneous absorption of 2-amino-4-nitrophenol in the rat

The absorption of ¹⁴C-labelled 2-amino-4-nitrophenol (ANP) in two hair dyeing formulations was investigated after application to the skin of rats. After 1 and 5 days, 0.21 and 0.36%, respectively, of the administered radioactivity was absorbed from formulation 1 which contained carboxymethylcellulose as a thickening agent. Absorption was greater (1.12% after 1 day, 1.67% after 5 days) from formulation 2 which contained oleic acid and isopropanol. Complementary studies of absorption after administration of [¹⁴C]ANP by sc injection or oral gavage were also carried out. The radioactivity was rapidly excreted, predominantly in the urine, in both cases. Biliary excretion was also detected in an oral study.     

Studies on Metabolism of Trazodone,I. Metabolic Fate of [14C]Trazodone Hydrochloride in Rats

Abstract

1. One of the main metabolites of [¹⁴C]trazodone hydrochloride by rat liver in vitro is hydroxylated trazodone.

2. [¹⁴C]Trazodone HCI is absorbed very rapidly and the blood level of radioactivity attains a maximum within 15 min after oral administration of 4 mg/kg to rats and thereafter decreases rapidly.

3. Urinary and faecal excretions of radioactivity are 49.0 and 46.1% of the dose respectively, during the first 7 days after ingestion, and biliary excretion is 80.0% in 8 h.

4. After oral administration of [¹⁴C]trazodone HCI to rats the main metabolites in urine and bile are hydroxylated trazodone, β-{3-oxo-s-triazolo[4,3a]-pyridin-2-yl}-propionic acid and their glucuronides.

5. Unchanged and hydroxylated trazodone alone are present in brain of rats after oral administration (20 mg/kg); both compounds in brain decrease with similar half-lives to those in plasma.     

Studies on the respiratory uptake and excretion and the skin absorption of methyl n-butyl ketone in humans and dogs

Methyl n-butyl ketone (MnBK) has produced peripheral neuropathy in experimental animals and is implicated in an occupationally produced neuropathy. Since occupational exposure to MnBK is by inhalation or skin contact, both the absorption and elimination of MnBK vapor and its absorption through skin were investigated. Studies were carried out first with male beagle dogs and subsequently with human volunteers. Humans exposed for 7.5 hours to 10 or 50 ppm or for 4 hr to 100 ppm of MnBK vapor absorbed between 75 and 92% of the inhaled vapor. Unchanged MnBK was not eliminated extensively in the postexposure breath or in urine. 2,5-Hexanedione, a metabolite of MnBK known to be neurotoxic in rats, was found in the serum of humans exposed to either 50 or 100 ppm of MnBK. The absorption and elimination of MnBK in dogs was similar to that observed in humans. The skin absorption of [1-¹⁴C]MnBK or a $\text{9}\text{1}$ ($\text{v}\text{v}$) mixture of methyl ethyl ketone $\text{(MEK)}\text{[1-}{}^{14}\text{C]MnBK}$ was determined by excretion analysis. Two volunteers exposed by skin contact to [1-¹⁴C]MnBK absorbed 4.8 μg min^?1 cm^?2 and 8.0 μg min^?1 cm^?2, respectively. Skin exposure to $\text{MEK}\text{[1-}{}^{14}\text{C]MnBK}$ resulted in the respective absorption of 4.2 and 5.6 μg min^?1 cm^?2 by two individuals. Two volunteers given an oral dose of [1-¹⁴C]MnBK (2 μCi; 0.1 mg/kg) excreted 49.9 and 29.0% of the dose, respectively, as respiratory ¹⁴CO₂ within 3 to 5 days and 27.6 and 25.0% of the dose, respectively, in urine within 8 days. Both [1-¹⁴C]MnBK and $\text{MEK}\text{[1-}{}^{14}\text{C]MnBK}$ were absorbed through the skin of dogs. These findings show that MnBK is readily absorbed by the lungs, the gastrointestinal tract, and through the skin, is not eliminated extensively unchanged in breath or urine, and is metabolized to CO₂ and 2,5-hexanedione. Radioactivity derived from [1-¹⁴C]MnBK was excreted slowly by man, suggesting that repeated daily exposure to high concentrations of MnBK may lead to a prolonged exposure to neurotoxic metabolites.     

Species variations in the N-oxidation of chlorphentermine

The metabolism and excretion of orally administered or injected [¹⁴C]chlorphentermine has been studied in man, rhesus monkey, marmoset, rabbit, guinea-pig and rat. These species excreted 55–95% of the administered radioactivity in the urine over 5 days. Two metabolites were characterised by thin-layer and paper chromatography, gas-liquid chromatography and g.c.-m.s. and these were N-hydroxychlorphentermine and 1-(4'-chlorophenyl)-2-methyl-2-nitropropane. There are marked species differences in the excretion of N-oxidation products which were found in the urine of human volunteers. rhesus monkeys, rabbits and guinea-pigs, but not in the urine of marmosets or rats. The rat, rabbit and marmoset also excreted an unidentified unstable acid-labile precursor of chlorphentermine. The results are discussed in relation to the toxicity of the drug and to the metabolism of amphetamines in general.     

The absorption, distribution and excretion of 1- and 2-.

Human breast milk is rich in 2-palmitoyl 1,3 unsaturated triacyglycerols and during the neonatal period, when milk is the sole source of nutrients, their role could be particularly important. Betapol is a novel triacylglycerol mix resembling human breast milk in its high palmitic acid content and positional distribution. The total fat absorption from Betapol has been shown to be higher than fat from conventional infant milk formulas and closer to human breast milk in infants. However, the relative fate of purified palmitic acid esterified to glycerol in the 1-, 3- and 2-positions in neonatal and young animals has not previously been established. Therefore, the fate of orally administered 1-[1-14C]palmitoyl, 2,3 dioleoyl glycerol ([14C]POO) and 1,3 dioleoyl,2-[1-14C]palmitoyl glycerol (O[14C]PO) was investigated in suckling and weanling rats using liquid scintillation counting of tissues and expired air and whole-body autoradiography. The results obtained indicate that orally administered [14C]POO and O[14C]PO are extensively absorbed from the gut, probably either as palmitic acid or as a palmitoyl glyceride in both suckling and weanling rats. Radioactivity initially concentrated in brown fat with apparent migration to the white fat of weanling rats by 96 h. Levels of 14C were low in blood, brain and other tissues. Excretion of 14C was mainly by expiration of CO(2) (approximately 72% in 96 h), indicating beta-oxidation as a major route of metabolism. Urine and faeces accounted for only approximately 6% of the excreted radioactivity. The design and size of the experiment did not allow tests of statistical significance between the absorption and excretion of OPO and POO to be conducted. However, the absorption, distribution, beta-oxidation and excretion appeared to be similar.